Review of Viral, Inflammatory and Proliferative Diseases
Diseases and disorders that have significant inflammatory, viral and/or proliferative components are widespread and affect millions of people worldwide. Selected examples of inflammatory, viral and/or proliferative diseases include multiple sclerosis, diabetes, restenosis, cancer, hepatitis B, hepatitis C, HIV/AIDS and genital warts. These types of diseases share common disease processes and as a result often share or possess related/common therapies.
Viral Diseases
Viruses are potent infectious pathogenic agents that cause important functional alterations of the invaded cells, often resulting in cellular death. It is generally acknowledged that the cell injury in viral diseases includes not only direct damages inflicted by the proliferation of viruses but also various immunologic reactions elicited by infection with viruses. The consequences of a viral disease depend upon several viral and host factors such as the quantity of infecting viral particles, the speed of viral multiplication and spread, the impact on cell functions, the host's secondary responses to the cellular injury, and both the immunologic and the non-specific defenses of the host. In general, the effects of a viral disease include asymptomatic infections, both acute and chronic clinical diseases and induction of various types of cancers. One example of a well known viral disease is viral hepatitis infection which results in chronic or acute inflammation of the liver and can lead to hepatocellular carcinoma in some cases. To date, there are several types of hepatitis viruses that have been identified including hepatitis viruses A, B, C, D, E and G; such viruses are prevalent among the population. For instance, it has been estimated by Liver Foundation International that there are more than 520 million individuals worldwide that suffer from either hepatitis B or hepatitis C.
Inflammatory Diseases
Inflammatory diseases are a class of diseases and disorders that are characterized by the influx of certain cell types and mediators, the presence of which can lead to tissue damage and sometimes death. Inflammatory diseases trigger what is known as the inflammatory cascade, a complex process that involves the triggering of immunological response, the release of chemokines, cytokines and toxic agents by the activated cells, the up-regulation of cell surface adhesion molecules and trans-endothelial cell migration. Typically, inflammation occurs as a defensive response to invasion of the host by foreign material, bacteria or to mechanical trauma, toxins and neoplasia. Autoimmune responses by intrinsic stimulation also can induce inflammatory responses.
One example of inflammatory disease is multiple sclerosis (“MS”). MS is a multi-factorial inflammatory disease of the human central nervous system resulting in the slowing of electrical conduction along the nerve. It is estimated that close to a third of a million people in the United States have MS. MS is believed to result from inflammation and breakdown in the myelin surrounding the nerve fibers of the central nervous system. The disease is characterized by an increase in the infiltration of inflammatory cells, loss of oligodendrocytes, and increased gliosis (astrocyte hypertrophy and proliferation). (For review see Amit et al., 1999; Pouly et al., 1999; Steinman et al., 1993; Miller, 1994).
Proliferative Diseases
Cancer is the most well known proliferative disease. Specifically, cancer is a generic term representing a collection of diseases arising from mutations of key molecules that regulate cell proliferation, invasion, and metastasis. The ability of tumor cells to metastasize involves deregulation via overproduction or mutation of genes that allow cells to invade out of the tissue of origin, survive in a contact-independent manner, escape immune recognition, lodge at a distant site, then invade to a suitable place within the new tissue and grow there. The molecules that are commonly involved in tumor initiation, progression and metastasis include adhesion molecules, growth factor receptors, factors regulating the cytoskeleton, master switches regulating cell cycle, proliferation repressor genes, proteases and transcription factors. The ability of most tumors to kill is directly related to their capacity to invade and ultimately to metastasize.
Viral, Inflammatory and Proliferative Diseases Share Common Disease Processes
There are several classes of molecules and disease processes that are common to viral, inflammatory, and proliferative diseases. These include elevated expression of adhesion molecules, cytokines and matrix metalloproteinases, increased cell proliferation and migration, increased inflammatory cell activation and infiltration, increased angiogenesis, and increased tissue destruction and dysfunctional matrix remodeling. Consequently, compounds for the treatment of these diseases are aimed at altering the immune system, cell proliferation, cell adhesion and migration, cytokine levels or activities or viral replication.
Interferons
Interferons are multi-functional cytokines that are capable of producing pleitrophic effects on cells, such as inhibition of virus replication (anti-viral effects), inhibition of cell proliferation (anti-proliferative effects) and inhibition of inflammation (anti-inflammatory effects). Because of these cellular responses to interferons, interferon-alpha and interferon-beta have been found to be clinically useful in the treatment of viral, proliferative and inflammatory diseases such as multiple sclerosis, hepatitis B/C and a number of cancers. Interferon therapies may also have potential use for the treatment of other inflammatory diseases, viral diseases and proliferative diseases.
Need for Enhancing Compounds to Decrease Side Effects
Although interferon compounds are used or potentially can be used to treat inflammatory, viral and proliferative diseases, these compounds have many undesirable side effects, which are exacerbated at high doses. These include local injection reactions, flu-like syndrome and depression. Accordingly, some patients are unable to tolerate the doses needed to achieve a therapeutic effect.
In addition, although many anti-viral, anti-inflammatory or anti-proliferative compounds may have shown promise in vitro against inflammatory, viral, or proliferative diseases, very high doses may be required in vivo; such doses often being toxic or causing severe side effects. Therefore, the limitation of these therapies may be in using sufficient levels of the compound to achieve maximal efficacy in the absence of side effects.
Thus, compounds that can be combined with anti-viral, anti-proliferative or anti-inflammatory compounds to increase effectiveness of treatments for inflammatory, viral or proliferative diseases are necessary. In addition, compounds that can reduce the doses and/or reduce frequency of administration to reduce side effects and to maintain or improve efficacy are necessary.
For example, a compound that can improve efficacy of interferon-beta in the treatment of MS would potentially reduce the amount and/or frequency of interferon-beta administration, reducing side effects induced by interferon-beta and possibly reducing the occurrence of neutralizing antibodies to interferon-beta in MS patients.
Neutralizing antibodies to interferon-beta occur in about one third of MS patients treated with interferon-beta and are positively correlated with a loss of therapeutic efficacy of interferon-beta Deisenhammer et al., 1999).
In addition, said compounds could not only enhance the efficacy in current or potential anti-viral, anti-proliferative or anti-inflammatory therapies but could also broaden use of these therapies into many other inflammatory, proliferative and viral diseases.
There have been reports of other therapeutic agents being tested in combination with interferon for treatment of inflammatory diseases such as multiple sclerosis. However, these combination therapies have resulted in limited efficacy or no reduction in side effects. For example, combination therapy comprising copaxone and interferon-alpha did not improve clinical scores in EAE-treated mouse (Brod et al., 2000). While novantrone, an anti-proliferative drug, is currently being tested in clinical trials for combination therapy with interferon-beta, novantrone is known to have a significant side effect profile including serious cardiac toxicity. Novantrone is restricted in its use because the risk of heart disease increases with the cumulative dose. According to the Food and Drug Administration, patients with MS should ordinarily not receive more than 8 to 12 doses of novantrone, administered over two to three years.
Accordingly, there is a need to develop therapies for viral, inflammatory or proliferative diseases that result in sufficient levels of anti-viral, anti-inflammatory and anti-proliferative compounds to achieve maximal efficacy with minimal side effects. There is a need to develop anti-viral, anti-inflammatory and anti-proliferative combination therapies for the treatment of viral, inflammatory or proliferative diseases wherein the combined elements have an enhancing therapeutic effect, while minimizing side effects.
Vitamin B12
Vitamin B12 is a cobalt-containing B complex vitamin that has various effects on biological processes in vivo. Vitamin B12 has a well-elucidated family of analogues and conjugates. Vitamin B12 compounds have been known to be involved in metabolic processes; and deficiency of vitamin B12 has been known to provoke pernicious anemia and neurological disorders. It is a co-factor essential in the metabolic pathway leading to synthesis of DNA, cell division, as well as cellular metabolism. Biochemical evidence suggests that vitamin B12 compounds may up-regulate gene transcription and thereby protein synthesis (Watanabe et al, 1994). It has been also suggested that vitamin B12 compounds play an important role in immune system regulation (Tamura et al, 1999, Sakane et al, 1982).
Specifically, vitamin B12 compounds have been suggested to possess some or limited anti-viral (Weinberg et al, 1995, 1998, Lott et al, 2001, Poydock, 1979, Tsao et al., 1990), anti-proliferative (Nishizawa et al, 1997, Shimizu, 1987, Poydock et al., 1979, 1985) and anti-inflammatory activities (U.S. Pat. No. 5,508,271, U.S. Pat. No. 5,964,224, U.S. Pat. No. 5,716,941) on their own. Vitamin B12 has also been tried in combination with other therapeutic agents (EP Patent # 0835660, U.S. Pat. No. 6,096,737) for the treatment of specific inflammatory diseases or proliferative diseases. However, to date, there has been no scientific evidence demonstrating an enhanced therapeutic effect of vitamin B12 in combination with interferon compounds for treatment of viral, inflammatory or proliferative disease.
It is therefore an object of the present invention to provide a combination therapy using vitamin B12 compounds with interferon compounds for the enhanced treatment of viral, inflammatory or proliferative diseases.